Control of human cytomegalovirus replication by liver resident natural killer cells

Natural killer cells are considered to be important for control of human cytomegalovirus– a major pathogen in immune suppressed transplant patients. Viral infection promotes the development of an adaptive phenotype in circulating natural killer cells that changes their anti-viral function. In contrast, less is understood how natural killer cells that reside in tissue respond to viral infection. Here we show natural killer cells resident in the liver have an altered phenotype in cytomegalovirus infected individuals and display increased anti-viral activity against multiple viruses in vitro and identify and characterise a subset of natural killer cells responsible for control. Crucially, livers containing natural killer cells with better capacity to control cytomegalovirus replication in vitro are less likely to experience viraemia post-transplant. Taken together, these data suggest that virally induced expansion of tissue resident natural killer cells in the donor organ can reduce the chance of viraemia post-transplant

Control of human cytomegalovirus replication by liver resident natural killer cells

Natural killer cells are considered to be important for control of human cytomegalovirus– a major pathogen in immune suppressed transplant patients. Viral infection promotes the development of an adaptive phenotype in circulating natural killer cells that changes their anti-viral function. In contrast, less is understood how natural killer cells that reside in tissue respond to viral infection. Here we show natural killer cells resident in the liver have an altered phenotype in cytomegalovirus infected individuals and display increased anti-viral activity against multiple viruses in vitro and identify and characterise a subset of natural killer cells responsible for control. Crucially, livers containing natural killer cells with better capacity to control cytomegalovirus replication in vitro are less likely to experience viraemia post-transplant. Taken together, these data suggest that virally induced expansion of tissue resident natural killer cells in the donor organ can reduce the chance of viraemia post-transplant

Control of human cytomegalovirus replication by liver resident natural killer cells

Abstract Natural killer (NK) cells are innate immune cells that have been suggested important for control of human cytomegalovirus (HCMV) – an important pathogen in immune suppressed transplant patients. In HCMV seropositive individuals a population of NK cells with adaptive features can expand in peripheral blood and has been shown to have enhanced antiviral function. This is particularly evident following solid organ transplant (SOT) where patients frequently experience episodes of HCMV viremia. In contrast, much less is understood about the identity and function of tissue-resident immune cells in the context of HCMV infection and pathogenesis. In this study, access to tissue-resident immune cells from human organs destined for transplant has enabled us to address this, for the first time. Here we show that human liver-resident (lrNK), like circulating NK (cNK) cells, express increased adaptive markers in HCMV+ individuals. Interestingly, lrNK demonstrated better control of HCMV replication in vitro when compared to cNK cells isolated from the same donor. Furthermore, this control phenotype was elevated if the cells were isolated from HCMV seropositive donors. Crucially, because these studies were performed on perfusates from livers destined for transplantation we could correlate a donor’s lrNK ability to control HCMV in vitro with a reduction in HCMV viraemia in liver transplant recipients in vivo. Finally, we demonstrate that a population of CD2+ NK cells are enriched in patients who did not develop viraemia post-transplant and that loss of control in vitro occurs when CD2 NK cells are depleted or inhibited with anti-CD2 antibodies. Therefore, lrNK have anti-viral activity that could be important for control of HCMV replication in tissue and contribute to better clinical outcomes following organ transplant. Understanding the importance of CD2 expressing populations could have implications for the development of novel therapies aimed at mobilising specific NK cell functions against infections and/or decreasing the ability of HCMV to evade NK responses.</jats:p

Control of human cytomegalovirus replication by liver resident natural killer cells

AbstractNatural killer cells are considered to be important for control of human cytomegalovirus– a major pathogen in immune suppressed transplant patients. Viral infection promotes the development of an adaptive phenotype in circulating natural killer cells that changes their anti-viral function. In contrast, less is understood how natural killer cells that reside in tissue respond to viral infection. Here we show natural killer cells resident in the liver have an altered phenotype in cytomegalovirus infected individuals and display increased anti-viral activity against multiple viruses in vitro and identify and characterise a subset of natural killer cells responsible for control. Crucially, livers containing natural killer cells with better capacity to control cytomegalovirus replication in vitro are less likely to experience viraemia post-transplant. Taken together, these data suggest that virally induced expansion of tissue resident natural killer cells in the donor organ can reduce the chance of viraemia post-transplant.</jats:p

Long-Term Persistence of Spike Protein Antibody and Predictive Modeling of Antibody Dynamics After Infection With Severe Acute Respiratory Syndrome Coronavirus 2

Abstract Background Antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been shown to neutralize the virus in vitro and prevent disease in animal challenge models on reexposure. However, the current understanding of SARS-CoV-2 humoral dynamics and longevity is conflicting. Methods The COVID-19 Staff Testing of Antibody Responses Study (Co-Stars) prospectively enrolled 3679 healthcare workers to comprehensively characterize the kinetics of SARS-CoV-2 spike protein (S), receptor-binding domain, and nucleoprotein (N) antibodies in parallel. Participants screening seropositive had serial monthly serological testing for a maximum of 7 months with the Meso Scale Discovery Assay. Survival analysis determined the proportion of seroreversion, while 2 hierarchical gamma models predicted the upper and lower bounds of long-term antibody trajectory. Results A total of 1163 monthly samples were provided from 349 seropositive participants. At 200 days after symptoms, &amp;gt;95% of participants had detectable S antibodies, compared with 75% with detectable N antibodies. S antibody was predicted to remain detectable in 95% of participants until 465 days (95% confidence interval, 370–575 days) using a “continuous-decay” model and indefinitely using a “decay-to-plateau” model to account for antibody secretion by long-lived plasma cells. S-antibody titers were correlated strongly with surrogate neutralization in vitro (R2 = 0.72). N antibodies, however, decayed rapidly with a half-life of 60 days (95% confidence interval, 52–68 days). Conclusions The Co-Stars data presented here provide evidence for long-term persistence of neutralizing S antibodies. This has important implications for the duration of functional immunity after SARS-CoV-2 infection. In contrast, the rapid decay of N antibodies must be considered in future seroprevalence studies and public health decision-making. This is the first study to establish a mathematical framework capable of predicting long-term humoral dynamics after SARS-CoV-2 infection. Clinical Trials Registration NCT04380896. </jats:sec